Successful prevention and treatment of alcohol use disorders depend on identifying factors that lead to excessive consumption and addictive behaviors. Yet, to date, the factors that lead from social drinking to alcohol abuse still are not clearly defined. Tolerance, sensitization, or both may be key factors in promoting excessive consumption. The development of these factors may initiate the dependence "downward spiral" that ultimately leads to adverse health consequences from alcohol toxicity. The proposed project will examine whether tolerance or sensitization alone is necessary and sufficient to promote alcohol consumption. Both of these behavioral phenomena result from complex neural adaptations to the drug. However, the neural adaptations that result in tolerance may occur at different rates, to different drug effects, and in different neural regions. Therefore, the goals of this project are threefold: To characterize the roles of different forms of tolerance on alcohol consumption;to assess whether manipulating tolerance will affect the development of sensitization;and to examine whether any co-dependency exists between the effect of tolerance and the effect of sensitization on alcohol consumption. Toward these goals, the project will employ: (i) co-administration of neurosteroids and alcohol to block or facilitate tolerance;(ii) a battery of behavioral tests to identify the presence or absence of tolerance and sensitization as a result of the pharmacological manipulations;and, (iii) a standardized consumption paradigm to assess effects on alcohol intakes. These findings will begin to uncover links between different systemic neural adaptations to alcohol and the independent and/or combined effects of those adaptations on alcohol consumption. If direct effects of tolerance are seen, these studies will pave the way for future studies to isolate region-specific tolerant adaptations (i.e., target brain regions or neurochemical substrates) that may be differentially facilitating progressive increases in alcohol intakes among abusers. PUBLIC HEALTH RELEVANCE: Alcoholics begin their careers with a single drink and, in time, their consumption patterns increase as a result of repeated exposures to the drug. The proposed project explores one of the consequences of those repeated exposures: tolerance. The central hypothesis is that tolerance promotes increased alcohol consumption. By doing so, tolerance may "kick start" the addiction cycle and enable the addict to achieve toxic intake levels that result in brain and organ damage. By providing insights into factors that cause excessive alcohol consumption and dependence, these studies will inform potential interventions and therapeutic targets.